New targeted therapies for breast cancer are needed for patients who do not have indication for targeted therapy (e.g: trastuzumab) in HER2 and/or ER negative tumors. The candidate has a strong background in basic and translational research in cancer biology and molecular therapeutics. She has shown that PEA-15, a novel phosphoprotein, has tumor suppressor properties;binds to ERK, blocking ERK activation. Her long-term goal is to be a independent translational researcher and to use targeted therapies to improve treatment options for patients with breast cancer. To become independent, she requires additional training in 5 areas: (1) training in Investigational New Drug (IND) and Patent applications to translate laboratory research into hypothesis-driven clinical trials;(2) identification of mouse models with most efficient knockdown using siRNA (3) metastasis assays, epithelial-to-mesenchymal transition (EMT) and angiogenesis;and (4) training in leadership skills. She has identified highly experienced co-mentors who are committed to helping her develop her skills in these areas. One is an expert in developing novel targeted therapies and the other has developed a novel liposomal in vivo siRNA delivery system. The central hypothesis is that suppressing ERK reduces tumorigenicity and metastasis in breast cancer. The 3 specific aims are: (1) Determine whether suppressing ERK inhibits tumorigenicity in HER2-negative breast cancer cells. (2) Determine the impact of ERK inhibition on EMT in HER2-negative breast cancer cells (3) Determine the role of the ERK modulator PEA-15 in HER2-negative breast cancer. Three different approaches will be used to suppress ERK: siRNA to knock down ERK, PEA-15 gene therapy to sequester ERK, and treatment with an inhibitor of MEK, which lies upstream of ERK. At the conclusion, she will determine if ERK pathway would be a useful molecular target for treatment of such disease. The candidate will use her extensive training to pursue independent research on ERK modulator resistance in tumorigenicity/metastasis, and development preclinical data which will lead to ERK targeted clinical trials in breast cancer. PUBLIC HEALTH RELEVANCE: Patients with HER2- or hormone receptor negative breast cancer cannot be successfully treated with hormonal therapy or the HER2-targeting agents, and they are at high risk for dying of metastatic disease. The proposed work has the potential to lead to the development of new targeted therapy for those breast cancer patients who do not have opportunity to received targeted therapies and thus to improve outcomes for women with this disease.